title: Darbepoetin-alpha prevents progressive left ventricular dysfunction and remodeling in nonanemic dogs with heart failure.
abstract: In anemic patients with heart failure (HF), erythropoietin-type drugs can elicit clinical improvement. This study examined the effects of chronic monotherapy with darbepoetin-alpha (DARB) on left ventricular (LV) function and remodeling in nonanemic dogs with advanced HF. HF [LV ejection fraction (EF) approximately 25%] was produced in 14 dogs by intracoronary microembolizations. Dogs were randomized to once a week subcutaneous injection of DARB (1.0 microg/kg, n=7) or to no therapy (HF, n=7). All procedures were performed during cardiac catheterization under general anesthesia and under sterile conditions. LV end-diastolic volume (EDV), end-systolic volume (ESV), and EF were measured before the initiation of therapy and at the end of 3 mo of therapy. mRNA and protein expression of caspase-3, hypoxia inducible factor-1alpha, and the bone marrow-derived stem cell marker c-Kit were determined in LV tissue. In HF dogs, EDV and ESV increased and EF decreased after 3 mo of followup. Treatment with DARB prevented the increase in EDV, decreased ESV, and increased EF. DARB therapy also normalized the expression of HIF-1alpha and active caspase-3 and enhanced the expression of c-Kit. We conclude that chronic monotherapy with DARB prevents progressive LV dysfunction and dilation in nonanemic dogs with advanced HF. These results suggest that DARB elicits beneficial effects in HF that are independent of the presence of anemia.
authors.affiliation: Department of Internal Medicine, Henry Ford Heart and Vascular Institute, Henry Ford Hospital, 2799 West Grand Blvd., Detroit, MI 48202, USA.
authors.forename: Sharad
authors.initials: S
authors.lastname: Rastogi
authors.forename: Makoto
authors.initials: M
authors.lastname: Imai
authors.forename: Victor G
authors.initials: VG
authors.lastname: Sharov
authors.forename: Sudhish
authors.initials: S
authors.lastname: Mishra
authors.forename: Hani N
authors.initials: HN
authors.lastname: Sabbah
mesh_terms: D000740:Anemia / Q000188:drug therapy / Q000209:etiology; D000818:Animals; D001854:Bone Marrow Cells / Q000473:pathology; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D000068256:Darbepoetin alfa; D004195:Disease Models, Animal; D018450:Disease Progression; D004285:Dogs; D004921:Erythropoietin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D006333:Heart Failure / Q000150:complications / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D006397:Hematinics / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000473:pathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D007279:Injections, Subcutaneous; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D013318:Stroke Volume / Q000187:drug effects; D018487:Ventricular Dysfunction, Left / Q000209:etiology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: D002316:Cardiotonic Agents; D006397:Hematinics; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D004921:Erythropoietin; D000068256:Darbepoetin alfa; D019009:Proto-Oncogene Proteins c-kit; D053148:Caspase 3